Aminomethyl-benzodioxane and benzopyran serotonergic agents

ABSTRACT

Certain aminomethyl-benzodioxanes and benzopyrans are useful serotonergic agents. They possess anxiolytic properties with few of the side effects often associated with dopaminergic agents.

This application is a divisional application of U.S. Ser. No.08/378,116, filed Jan. 24, 1995, now U.S. Pat. No. 5,496,847, which wasa division of U.S. Ser. No. 08/136,521 filed Oct. 14, 1993 and is nowU.S. Pat. No. 5,391,570.

BACKGROUND

This invention generally pertains to aminomethyl-benzodioxane andbenzopyran compounds having anxiolytic, antidepressant and otherpsychotropic, bio-affecting properties and to their preparation and use.

In some preferred embodiments, the invention is concerned with1,3-benzodioxo-5-yl-4-hydroxycyclohexyl or1,3-benzodioxo-5-yl-4-methoxy-cyclohexyl derivatives of these compounds.These compounds, and others structurally related thereto, possess aunique serotonergic profile that makes them useful in the treatment ofanxiety and depression.

Lednicer discloses, in U.S. Pat. No. 3,965,180, a series oftranquilizers of

Formula A. Formula A is: ##STR1## wherein: R_(a) is lower alkyl,halogen, trifluoromethyl or lower alkoxy;

R_(b) is H or R;

R_(c) is lower alkyl,

R_(d) is H or lower alkyl, and

R_(e) is H, lower alkyl or substituted aroylalkyl.

The bonds linking the benzene ring and/or R_(c) O with the cyclohexenering may have cis, trans or mixed configurations.

As can be seen, these earlier compounds are chemically distinguishablefrom the instant compounds on the basis of their chemical structuresbecause they are alkyl-, halo-, halomethyl or alkoxybenzyl cyclohexanes,whereas the instant compounds are benzodioxo- orbenzodioxanyl-cyclohexanes. Furthermore, neither R_(d) nor R_(e) inLednicer's structure may be aminomethyl-benzopyran oraminomethyl-benzodioxane residues, as applicants' Formula I (below)requires.

All publications referred to herein are hereby incorporated byreference.

DESCRIPTION OF THE INVENTION

In its broadest aspect, the invention is concerned with certaincompounds which are substituted aminomethyl-benzodioxanes andbenzopyrans. The compounds, which are useful anxiolytic andantidepressant agents, conform to Formula I: ##STR2## wherein: R¹ and R²are both halogen or, taken together, form a --O--(CH₂)_(n) --O-- bridge(n=1, 2 or 3);

Cy is either ##STR3## (m=0, 1 or 2), with the phenyl substituent at the1 position of the cycloalkanyl or cycloalkenyl ring and the aminosubstituent at the 4 position;

R³ and R⁴ are independently H or C₁₋₄ alkyl; and

Y is O, CH₂, N or S.

Compounds of Formula I include all pharmaceutically acceptable saltsand/or solvates thereof. The invention also encompasses allstereoisomers of compounds of Formula I.

Pharmaceutically acceptable salts, amides and hydrates based on FormulaI can be obtained using inorganic or organic acids such as sulfuric,phosphoric, hydrochloric, hydrobromic, hydroiodic, citric, acetic,benzoic, fumaric, cinnamic, mandelic, nitric, mucic, isethionic,palmitic, heptanoic and the like. Fumarate and hemifumarate salts arehighly useful, as are acetates and hydrates.

While R¹ and R² may both be halogen or taken together are --O--(CH₂)_(n)--O--, wherein n is 1, 2, or 3, it is generally preferred that R¹ and R²are both fluorine or that they are parts of a ring in which n is 1.

While Cy may be either a cycloalkanyl or a cycloalkenyl linkage, thecycloalkanyl linkage is highly preferred. It is also preferred that m be1.

While R³ and R⁴ may both be hydrogen or C₁₋₄ moieties, it is generallypreferred that only one of them be alkyl. Preferred alkyl groups arethose that contain not more than two carbon atoms. Thus, methyl andethyl groups are preferred embodiments for R³ or R⁴, when either is nothydrogen.

n is the integer 1, 2 or 3. In preferred embodiments, n is 1 or 2. Inhighly preferred embodiments, n is 1.

Y may be O, CH₂, N or S. In preferred embodiments, Y is O or CH₂, with Obeing highly preferred.

Preferred compounds of Formula I are:

Cis-4-[(2S-1,4-benzodioxan-2-yl)methylamino]-1-(1,3-benzodioxol-5-yl)cyclohexanol;

Cis-N-[4-(1,3-benzodioxol-5-yl)-4-methoxycyclohexyl]-2S-1,4-benzodioxane-2-methanaminehemifumarate;

(±)-Cis-4-[[(1,4-benzodioxan-2-yl)methyl]amino]-1-(1,3-benzodioxol-5-yl)cyclohexanolhydrate;

(±)-Cis-N-[4-(1,4-benzodioxan-6-yl)-4-methoxycyclohexyl]-1,4-benzodioxane-2-methanaminehemifumarate;

(±)-Cis-N-[4-(1,3-benzodioxol-5-yl)-4-ethoxycyclohexyl]-1,4-benzodioxane-2-methanaminefumarate;

(±)-Cis-N-[4-(1,3-benzodioxol-5-yl)-4-methoxycyclohexyl]-1,4-benzodioxane-2-methanaminehemifumarate;

(±)-Cis-N-ethyl-N-[4-(1,3-benzodioxol-5-yl)-4-hydroxycyclohexyl]-1,4-benzodioxane-2-methanaminefumarate;

(±)-Cis-N-methyl-N-[4-(1,3-benzodioxol-5-yl)-4-methoxycyclohexyl]-1,4-benzodioxane-2-methanaminefumarate;

(-)-(R)-Cis-N-[4-(1,3-benzodioxol-5-yl)-4-methoxycyclohexyl]-1,4-benzodioxane-2-methanaminefumarate;

(±)-Trans-N-[4-(1,3-benzodioxol-5-yl)-4-methoxycyclohexyl]-1,4-benzodioxane-2-methanaminehemifumarate;

(±)-Cis-4-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]amino]-1-(1,3-benzodioxol-5-yl)cyclohexanol;

N-[4-(1,3-benzodioxol-5-yl)-3-cyclohexen-1-yl]-2S-1,4-benzodioxane-2-methanamine;and

(±)-Cis-4-[(1,4-benzodioxan-2-yl)methylamino]-1-(3,4-difluorophenyl)cyclohexanol.

Another aspect of the present invention is a method for treating amammal afflicted with anxiety or panic disorders which comprisesadministering systematically to said mammal a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable acidaddition salt, amide, hemihydrate, or hydrate thereof.

The dosage regimen must in each case be carefully adjusted, utilizingsound professional judgment and considering the age, weight andcondition of the recipient, the route of administration and the natureand gravity of the illness. Generally, the daily dose will be from about0.01 to about 10 mg/kg, preferable 0.1 to 2 mg/kg, when administeredparenterally and from about 1 to 50 mg/kg, when administered orally. Insome instances, a sufficient therapeutic effect can be obtained at lowerdoses while in others, greater doses will be required.

Systemic administration refers to oral, rectal, transnasal, transdermal,and parenteral (i.e., intramuscular, intravenous, and subcutaneous)routes. Generally, when a compound is administered orally, a greaterquantity of the active agent is required to produce the same effect as asimilar quantity given parenterally. In accordance with good clinicalpractice, it is preferred to administer the present compounds at aconcentration level that will produce effective anxiolytic effectswithout causing any harmful or untoward side effects.

The compounds of the present invention may be administered foranxiolytic purposes, either as individual therapeutic agents or inmixtures with other therapeutic agents. Therapeutically, they aregenerally given as pharmaceutical compositions comprised of ananxiolytic amount of a compound of Formula I or a pharmaceuticallyacceptable derivative thereof and a pharmaceutically acceptable carrier.Pharmaceutical compositions which provide from about 1 to 500 mg of theactive ingredient per unit dose are preferred and are conventionallyprepared as tablets, lozenges, capsules, powders, aqueous or oilysuspensions, syrups, elixirs, and aqueous solutions.

The nature of the pharmaceutical composition employed will, of course,depend on the desired route of administration. For example, oralcompositions may be in the form of tablets or capsules and may containconventional excipients such as binding agents (e.g., starch) andwetting agents (e.g., sodium lauryl sulfate). Solutions or suspensionsof one or more Formula I compounds with conventional pharmaceuticalvehicles are employed for parenteral compositions, such as aqueoussolutions for intravenous injection or oily suspensions forintramuscular injection.

The reaction schemes and biological data set out hereafter refer to asampling of the compounds of the invention.

PREPARATION

The intermediate ketones, i-a and i-b, are prepared as shown below.Reaction of cyclohexan-1,4-dione mono-ethyleneketal with organometallicreagents, such as Grignard reagents, aryl lithium reagents and the like,furnish the 4-aryl-4-hydroxy-cyclohexanone ketals, ii. These reactionsare generally carried out in solvents such as tetrahydrofuran, diethylether, dimethoxyethane, dioxane, ethylene glycol dimethylether and thelike at temperatures from -80° to 30° C. The ketals are cleaved underacidic conditions in a solvent such as methanol, ethanol, 2-propanol,acetone, tetrahydrofuran, dioxane, dimethoxyethane, acetonitrile,dichloromethane, 1,2-dichloroethane and the like to give the4-aryl-4-hydroxycyclohexanones, i-a. Acids suitable for this hydrolysisinclude but are not limited to hydrochloric, sulfuric, acetic,phosphoric, para-toluenesulfonic, methanesulfonic, benzoic and the like.##STR4##

The hydroxycyclohexanones, i-a, can be reacted in an alcoholic solutionwith a strong acid such as sulfuric acid, p-toluene sulfonic acid, orthe like, followed by mild acidic hydrolysis as described above to givethe alkoxycyclohexanones, i-b. Alternatively the cyclohexanols, ii, canbe reacted with an alkylating agent and an appropriate base in asuitable solvent such as tetrahydrofuran, diethyl ether,dimethylformamide, dimethylacetamide, dimethyl sulfoxide, dioxane,dimethoxyethane, ethylene glycol dimethyl ether and the like to give theethers, iii. Appropriate bases for this reaction include but are notlimited to sodium hydride, potassium hydride, calcium hydride, lithiumhydride, sodium carbonate, potassium carbonate, sodium hydroxide,potassium hydroxide, calcium hydroxide, butyl lithium, methyl lithium,phenyl lithium and the like. Alkylating agents include, but are notlimited to, methyl iodide, ethyl iodide, dimethyl sulfate, diethylsulfate, propyl iodide, propyl bromide, methyltrifluoro-methanesulfonate, ethyl trifluoromethanesulfonate, methyltrifluoroacetate, ethyl trifluoroacetate, and the like. Further mildacid hydrolysis of iii by the methods described above yields thealkoxycyclohexanones, i-b.

The aminomethyl-benzopyran, iv-a (Y=CH₂), was prepared from thecorresponding carboxylic acid, v, in 4 steps as shown below. The acid,v, may be reduced to the alcohol with a suitable reducing agent, such asLiAlH₄, AlH₃, B₂ H₆, or the like. The intermediate alcohol is thenactivated by conversion to the alkyl halide, sulfonate ester, or thelike, to give intermediate vi. Subsequent reaction of vi under standardconditions with azide, followed by hydrogenation over a catalyst such aspalladium on carbon, provides the aminomethyl-benzopyran, iv-a (Y=CH₂).Alternatively, vi can be used to alkylate an imide such as phthalimide,succinimimde or the like. Subsequent cleavage of the imide usingreagents such as hydrazine or sodium hydroxide also provides theaminomethyl-benzopyran, iv-a (Y=CH₂). Both optical isomers of theaminomethyl-benzodioxane fragment, iv-b (Y=O), were steriospecificsynthesized by the method of Nelson and Wennerstrom (J. Med. Chem, 1977,20, 800). ##STR5##

The cyclohexanones, i, may be reductively coupled with the amines, iv,to provide the compounds of Formula I as a mixture of cis and transcyclohexane isomers which can be separated by methods known to thoseskilled in the art, such as chromatography, recrystallization, and thelike. Reagents suitable for this reductive coupling include but are notlimited to sodium borohydride, sodium cyanoborohydride, sodiumtriacetoxyboro-hydride, sodium borohydride/titanium isopropoxide, sodiumcyanoborohydride/titanium isopropoxide and the like. The reductivelycoupling is generally run in a solvent such as ethanol, methanol,tetrahydrofuran, dioxane, dichloromethane, 1,2-dichloroethane,dimethoxyethane, and the like, at temperatures of 25° to 100° C. Apreferred method of coupling the two fragments, i and iv, consists ofrefluxing them in a solvent such as benzene, toluene, or cyclohexane,until the elimination of water is complete. Subsequent reduction withsodium borohydride in alcoholic solvents yields essentially allcis-cyclohexane product, Ia (cis). ##STR6##

The N-alkyl groups, R⁴, may be reductively added to compounds of FormulaI using aldehydes and ketones with reducing agents such as thosedescribed above. Alternatively the N-alkyl groups can be added by simplealkylation using alkylating agents and an appropriate bases in suitablesolvents such as those described above. ##STR7##

Treatment with strong acid converts the cyclohexanols and cyclohexylethers of Formula I to the corresponding cyclohexenes (Ib) as shownbelow. Alternatively, reagents such as POCl₃, SOCl₂, or the like, insolvents such as, e.g., pyridine, may also be used for this conversion.##STR8##

EXAMPLES

The compounds which constitute this invention, their methods ofpreparation and their biological actions will be better appreciatedafter consideration of the following examples, which are given for thepurpose of illustration only and are not be construed as limiting theinvention. In the following examples, temperatures are expressed indegrees Celsius (°C.) and melting points are uncorrected. Unless statedotherwise, all percentages given herein are weight percentages based ontotal composition weight.

The following examples describe in detail the preparation of compoundsof Formula I, as well as Formula II synthetic intermediates in eachprocess. It will be apparent to those skilled in the art thatmodifications, both of materials and methods, will allow preparation ofother compounds disclosed herein.

A. Preparation of intermediate compounds

Some representative procedures for preparation of synthetic intermediatecompounds utilized above are given herein below. Most starting materialsand certain intermediates are either commercially available orprocedures for their synthesis are readily available in the chemicalliterature, allowing their full utilization by one skilled in the art oforganic synthetic chemistry.

Intermediate 1: 8-(1,3-Benzodioxol-5-yl)-1,4-dioxaspiro[4.5]decan-8-ol

A solution of 1,4-cyclohexanedione monoethylene ketal (31.2 g, 0.2 mole)in 100 ml dry THF was added to a -60° C. solution of the Grignardreagent prepared from magnesium metal (7.2 g, 0.3 mole) and5-bromo-1,3-benzodioxole (60.3 g, 0.3 mole). The mixture was allowed towarm to 25° C. and quenched with saturated NH₄ Cl and extracted withether. The extracts were dried with Na₂ SO₄ and the solvent removed invacuo. The residue was crystallized from isopropyl ether to give theproduct (47.5 g, 85%, m.p: 103°-104° C.).

Intermediate 2: 4-(1,3-benzodioxol-5-yl)-4-hydroxycyclohexanone

A solution of 8-(1,3-benzodioxol-5-yl)-1,4-dioxaspiro[4.5]decan-8-ol(IIIb; 5 g, 18 mmole) in 75 ml acetone, 1 ml 12N HCl, and 50 ml water,was stirred for 2 hr. After dilution with an additional 50 ml water thesolid was collected to give the product (4.0 g, 95%, mp: 166°-168° C.).

Intermediate 3: 4-(1,4-benzodioxan-6-yl)-4-hydroxycyclohexanone

A solution of 1,4-cyclohexanedione monoethylene ketal (7.8 g, 50 mmole)in 50 ml dry THF was added to a of the Grignard reagent prepared frommagnesium metal (1.34 g, 55 mmole) and 6-bromo-1,4-benzodioxane (10.75g, 50 mmole). The mixture was stirred for 16 hr, quenched with saturatedNH₄ Cl and extracted with ether. The ether extracts were dried with Na₂SO₄ and the solvent removed in vacuo. Acetone (75 ml) and 1N HCl (75 ml)were added and the solution was stirred 18 hr to give a tan precipitatewhich was filtered and air dried (6.38 g, 59.1%). This material was usedwithout further purification.

Intermediate 4: 4-(1,3-Benzodioxol-5-yl)-4-methoxycyclohexanone

A solution of 8-(1,3-Benzodioxol-5-yl)-1,4-dioxa-spiro[4.5]decan-8-ol(5.0 g, 1.8 mmole) in 100 mL methanol with 1 mL conc. hydrochloric acidwas stirred for 22 hr and the solution concentrated in vacuo. Theresidue was purified by chromatography on silica eluting with ethylacetate-hexane (1:19) to give the product (70%, mp: 84°-85° C.).

Calc'd for C₁₄ H₁₆ O₄ : C, 67.73%; H, 6.50%. Found: C, 67.25%; H, 6.56%.

Intermediate 5: 8-(3,4-Difluorophenyl)-1,4-dioxaspiro[4.5]decan-8-ol

This compound was prepared from 1,4-cyclohexanedione monoethylene ketal(15.6 g, 100 mmole) and 3,4-difluorophenyl magnesium bromide (100 mmole)in the usual manner. The crude product was crystallized from isopropylether to give the product (42%, mp: 118°-120° C.).

Calc'd. for C₁₄ H₁₆ F₂ O₃ : C, 62.22%; H, 5.97%. Found: C, 61.97%; H,6.35%.

Intermediate 6: 4-(3,4-Difluorophenyl)-4-hydroxycyclohexanone

A solution of 8-(3,4-difluorophenyl)-1,4-dioxaspiro[4.5]decan-8-ol (5.4g, 20 mmole) in acetone-1N hydrochloric acid (1:1) was stirred for 4 hr.The acetone was removed in vacuo and the crude material crystallizedfrom isopropyl ether to give the product (62%, mp: 84°-85° C.).

Calc'd. for C₁₂ H₁₂ F₂ O₂ : C, 63.72%; H, 5.35%. Found: C, 62.72%; H,5.24%.

Intermediate 7: (±)-[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]amine

LAH pellets (3.2 g, 84.3 mmole) were added slowly to a stirred solutionof 3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (15 g, 84.3 mmole) inTHF (150 ml). After the vigorous reaction subsided, the mixture wasrefluxed for 1 hr and then cooled. To the hot mixture were addedsequentially, H₂ O (3.2 ml), 15% NaOH (3.2 ml), and then H₂ O (12.8 ml).The mixture was filtered and the filter cake washed with THF. The THFfiltrate was concentrated in vacuo, and Kugelrohr distilled to a clearoil (13.85 g, 100%). This alcohol intermediate was stirred in SOCl₂ for18 hr. The excess SOCl₂ was removed in vacuo and the resulting dark oilwas Kugelrohr distilled to a clear oil (8.65 g, 56.2%). This alkylchloride intermediate was heated to 100° in DMF with NaN₃ (4.32 g, 66mmole) and KI (0.2 g) for 72 hr. The mixture was diluted with H₂ O (250ml) and extracted with CH₂ Cl₂ three times. The CH₂ Cl₂ extracts wereconcentrated in vacuo. The residue was hydrogenated at 60 psi over 10%Pd/C (1 g) in ethanol and 37% HCl (10 ml) for 3 hr. H₂ O (20 ml) wasadded and the mixture was filtered. The ethanol was removed in vacuo andthe aqueous residue was made basic with 10N NaOH. The mixture wasextracted three times with ethyl acetate (50 ml portions). The extractswere concentrated in vacuo and the tan oil was Kugelrohr distilled to aclear oil (6.35 g, 82.2%). The product was used without furtherpurification.

B. Preparation of Compounds of Formula I

Example 1Cis-4-[(2S-1,4-Benzodioxan-2-yl)methylamino]-1-(1,3-benzodioxol-5-yl)cyclohexanol

A mixture of 2S-aminomethyl-1,4-benzodioxane (1.4 g, 8.5 mmole) (J. B.Stenlake, J. Pharm. Pharmac, 1968, 20, Suppl., 82S),6-(1,3-benzodioxol-5-yl)-6-hydroxycyclohexanone (2.0 g, 8.5 mmole) andtitanium isopropoxide (5 ml) was warmed slightly until a clear mixformed. After stirring for 2 hr no carbonyl absorption was observed inthe IR and the mix was dissolved in ethanol (50 ml). Sodium borohydride(0.4 g, 10 mmol) was added and the mixture stirred for 4 hr. The mixturewas hydrolyzed with 15% NaOH solution (20 ml). The insolubles wereremoved and the solution concentrated in vacuo. The residue wasdissolved in ether and the solution washed with 1N HCl. The acid washeswere basified with NaOH solution and the basic mixture extracted withmethylene chloride. The extracts were dried over sodium sulfate andconcentrated in vacuo. The residue was crystallized from ether to givethe product as a white solid (81%, mp: 110°-111° C.).

Calc'd for C₂₂ H₂₅ NO₅ : C, 68.92%; H, 6.58%; N, 3.66%. Found: C,69.03%; H, 6.65%; N, 3.72%.

Example 2Cis-N-[4-(1,3-Benzodioxol-5-yl)-4-methoxycyclohexyl]-2S-1,4-benzodioxane-2-methanaminehemifumarate

A mixture of titanium isopropoxide (3.5 ml),6-(1,3-benzodioxol-5-yl)-6-methoxycyclohexanone (1.23 g, 4.96 mmole) and2S-aminomethyl-1,4-benzodioxane (0.82 g, 4.96 mmole) was warmed for 1hr. The melt was dissolved in ethanol (50 ml) and sodium borohydride(0.6 g, 15 mmol) was added. After stirring for 18 hr the mixture washydrolyzed with 15% NaOH solution and the insolubles removed and washedwith acetone. The solution was concentrated in vacuo and the residuepurified by chromatography on silica eluting with methanol in methylenechloride (2%) to give 1:1 of product as an oil. The material wasdissolved in acetone and fumaric acid (0.32 g) was added to give thefumarate salt (56%, mp: 208°-209° C.).

Calc'd for C₂₃ H₂₇ NO₅.O.5 C₄ H₄ O₄ : C, 65.93%; H, 6.42%; N, 3.08%.Found: C, 66.02%; H, 6.50%; N, 3.08%.

Example 3(±)-Cis-4-[[(1,4-benzodioxan-2-yl)methyl]amino]-1-(1,3-benzodioxol-5-yl)cyclohexanolhydrate

This compound was prepared in a manner similar to that used in Example1, using racemic starting material. This racemic product was purified bychromatography on silica gel using 5% methanol/ethyl acetate to give awhite powder (47.4%, mp: 114°-116° C.).

Calc'd for C₂₂ H₂₅ NO₅.O.11H₂ O: C, 68.55%; H, 6.60%; N, 3.63%. Found:C, 68.55%; H, 6.54%; N, 3.58%.

Example 4(±)-Cis-N-[4-(1,4-benzodioxan-6-yl)-4-methoxycyclohexyl]-1,4-benzodioxane-2-methanaminehemifumarate

This compound was prepared in a manner similar to that used in Example2, using racemic aminomethyl-1,4-benzodioxane and 4(1,4-benzodioxan-6-yl)4-methoxycyclohexanone (prepared in a mannersimilar to Intermediate 4). The racemic product was purified bychromatography on silica gel using 5% methanol/ethyl acetate and thenconverted to the hemifumarate salt in acetonitrile to give a whitepowder (64.3%, mp: 201°-202.5° C.).

Calc'd for C₂₄ H₂₉ NO₅.O5 C₄ H₄ O₄ : C, 66.51%; H, 6.66%; N, 2.98%.Found: C, 66.46%; H, 6.69%; N, 2.94%.

Example 5(±)-Cis-N-[4-(1,3-benzodioxol-5-yl)-4-ethoxycyclohexyl]-1,4-benzodioxane-2-methanaminefumarate

This compound was prepared in a manner similar to Example 2 usingracemic aminomethyl-1,4-benzodioxane and4-(1,3-benzodioxol-5-yl)-4-ethoxy-cyclohexanone (prepared in a mannersimilar to Intermediate 4). The racemic product was purified bychromatography on silica gel using 5% methanol/ethyl acetate and thenconverted to the fumarate sale in acetonitrile to give a white powder(46.6%, mp: 184°-195° C.).

Calc'd for C₂₄ H₂₉ NO₅.O.7 C₄ H₄ O₄ : C, 65.32%; H, 6.51%; N, 2.84%.Found: C, 65.20%; H, 6.49%; N, 2.80%.

Example 6(±)-Cis-N-[4-(1,3-Benzodioxol-5-yl)-4-methoxycyclohexyl]-1,4-benzodioxane-2-methanaminehemifumarate

A cyclohexane solution (50 ml) of4-(1,3-benzodioxol-5-yl)-4-methoxycyclo-hexanone (2.48 g, 10 mmole) andracemic aminomethyl-1,4-benzodioxane (1.65 g, 10 mmole) were refluxedunder a Dean-Stark trap for 2.5 hr. The solvent was removed in vacuo,and the crude imine washed with diisopropyl ether to give a white powder(3.33 g, 84.3%). The imine intermediate (3.00 g, 7.595 mmole) wasdissolved in ethanol (30 ml) and then reduced for 18 hr with sodiumborohydride (four 0.15 g tablets, 16 mmole). The ethanol was removed invacuo and the residue dissolved in ethyl acetate. After extraction withwater and saturated sodium carbonate, the ethyl acetate layer wasconcentrated in vacuo to give a light yellow oil. This crude product wasconverted to the hemifumarate salt in ethyl acetate to give a whitepowder (78.4%, mp: 202°-203° C.).

Calc'd for C₂₃ H₂₇ NO₅.O.5 C₄ H₄ O₄ : C, 65.92%; H, 6.42%; N, 3.08%.Found: C, 66.12%; H, 6.41%; N, 3.08%.

Example 7(±)-Cis-N-Ethyl-N-[4-(1,3-benzodioxol-5-yl)-4-hydroxycyclohexyl]-1,4-benzodioxane-2-methanamine fumarate

A solution of(±)-Cis-N-[4-(1,3-benzodioxol-5-yl)-4-methoxycyclohexyl]-1,4-benzodioxane-2-methanamine(1.0 g, 2.245 mmole), sodium cyanoborohydride (0.62 g, 10 mmole), andacetaldehyde (2 ml, 36 mmole) in ethanol (15 ml) was stirred for 48 hr,and then refluxed for 2 hr. The reaction mixture was filtered andconcentrated in vacuo. The residue was dissolved in ethyl acetate andextracted with water and brine. The ethyl acetate extract wasconcentrated in vacuo to give the crude oil which was purified bychromatography on silica gel using 5% to 20% methanol/ethyl acetate asthe eluent to give a clear oil (0.86 g, 82.6%). This free base wasdissolved in acetonitrile (40 ml) and 12N HCl (0.25 ml) was added togive the HCl salt as a white powder (0.66 g, 65.5% overall yield, mp:181°-183.5° C.).

Calc'd for C₂₄ H₂₉ NO₅.HCl: C, 64.35%; H, 6.75%; N, 3.13%. Found: C,64.75%; H, 6.75%; N, 3.27%.

Example 8(±)-Cis-N-Methyl-N-[4-(1,3benzodioxol-5-yl)-4-methoxycyclohexyl]-1,4-benzodioxane-2-methanaminefumarate

(±)-Cis-N-[4-(1,3-benzodioxol-5-yl-4-methoxycyclohexyl]-1,4-benzodioxane-2-methanaminewas converted to this compound in a reaction similar to Example 7 usingsodium cyanoborohydride and formaldehyde in ethanol. The crude oil wastreated with fumaric acid in ethyl acetate, but a solid salt failed toform. The ethyl acetate was removed in vacuo, and the glassy productwashed with ether. The product was partitioned between ethyl acetate andsaturated sodium carbonate to give the free base. The ethyl acetateextract was concentrated in vacuo to a clear oil that solidified uponstanding. This solid was recrystallized from 10% ethyl acetate/hexane togive a white powder (44.5%, mp: 114.5°-117° C.).

Calc'd for C₂₄ H₂₉ NO₅ : C, 70.05%; H, 7.10%; N, 3.40%. Found: C,70.04%; H, 7.09%; N, 3.38%.

Example 9(-)-(R)-Cis-N-[4-(1,3-benzodioxol-5-yl)4-methoxycyclohexyl]-1,4-benzodioxane-2-methanaminefumarate

This compound was prepared in a manner similar to Example 2 using2R-aminomethyl-1,4-benzodioxane. The product was purified bychromatography on silica gel using 5-20% methanol/ethyl acetate to givea clear oil, which was converted to the hemifumarate salt as a whitepowder (27.9%, mp: 202°-203° C.).

Calc'd for C₂₃ H₂₇ NO₅.O.5 C₄ H₄ O₄ : C, 65.92%; H, 6.42%; N, 3.08%.Found: C, 65.77%; H, 6.21%; N, 3.03%.

Example 10(±)-Trans-N-[4-(1,3-benzodioxol-5-yl)-4-methoxycyclohexyl]-1,4-benzodioxane-2-methanaminehemifumarate

A solution of cyclohexane (35 ml),4-(1,3-benzodioxol-5-yl)-4-methoxy-cyclohexanone (2.48 g, 10 mmole) andracemic aminomethyl-1,4-benzodioxane (1.65 g, 10 mmole) were refluxedunder a Dean-Stark trap for 4 hr. The solvent was removed in vacuo, andthe crude imine was dissolved in THF (40 ml) and then stirred for 3 dayswith sodium triacetoxyborohydride (3.40 g, 16 mmole). The solvent wasremoved in vacuo and the residue dissolved in ethyl acetate. Afterextraction with water and saturated sodium carbonate, the ethyl acetatelayer was concentrated in vacuo to give a light yellow oil. This crudemixture of cis and trans cyclohexyl isomers was separated bychromatography on silica gel using 25-100% ethyl acetate/hexanes to givethe less polar trans product (1.29 g, 37.6%) and the more polar cisproduct (1.36 g, 42.5%, previously described in Example 6). The lesspolar trans product was converted to the fumarate salt in methanol/ethylacetate (mp: 171°-173° C.).

Calc'd for C₂₃ H₂₇ NO₅.C₄ H₄ O₄ : C, 63.15%; H, 6.09%; N, 2.73%. Found:C, 63.07%; H, 6.04%; N, 2.65%.

Example 11(±)-Cis-4-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]amino]-1-(1,3-benzodioxol-5-yl)cyclohexanol

This compound was prepared from(±)-[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]amine and4-(1,3-benzodioxol-5-yl)-4-hydroxycyclohexanone in a manner similar toExample 1 to give the crude product. This racemic product was purifiedby chromatography on silica gel using 0-10% methanol/ethyl acetate togive a white powder (34.9%, mp: 135°-137° C.).

Calc'd for C₂₃ H₂₇ NO₄ : C, 72.42%; H, 7.14%; N, 3.67%. Found: C,72.13%; H, 7.10%; N, 3.69%.

Example 12N-[4-(1,3-Benzodioxol-5-yl)-3-cyclohexen-1-yl]-2S-1,4-benzodioxane-2-methanamine

A solution ofcis-N-[4-(1,3-benzodioxol-5-yl)-4-methoxycyclohexyl]-2S-1,4-benzo-dioxan-2-methanaminein etherethanol was acidified with conc HCl. A solid separated and wasconverted to the free base. The material was purified by chromatographyon alumina eluting with ethyl acetate in hexane (1:4) to give theproduct (10%, mp: 90°-92° C.).

Calc'd for C₂₂ H₂₃ NO₄.O.5H₂ O: C, 71.60%; H, 6.40%; N, 3.80%. Found: C,71.67%; H, 6.38%; N, 3.80%.

Example 13(±)-Cis-4-[(1,4-Benzodioxan-2-yl)methylamino]-1-(3,4-difluorophenyl)cyclohexanol

A mixture of 1,4-benzodioxane-2-methanamine (0.5 g, 2.5 mmole),4-(3,4-difluoro-phenyl)-4-hydroxycyclohexanone (0.56 g, 2.5 mmole) andtitanium isopropoxide (0.9 ml, 3 mmole) in a minimum volume ofdichloromethane was stirred under nitrogen. After stirring for 18 hr nocarbonyl absorption was observed in the IR and the mixture was dissolvedin ethanol (10 ml). Sodium borohydride (0.1 g, 2.5 mmol) was added andthe mixture was stirred for 3 hr. The mixture was hydrolyzed with 15%NaOH solution (5 ml). The mixture was filtered and the filtrateconcentrated in vacuo. The residue was dissolved in ether and thesolution shaken with 1N HCl to give the product as the hydrochloride.The salt was collected and crystallized from 2-propanol/hexane (70%, mp:254°-256° C.).

Calc'd for C₂₁ H₂₃ F₂ NO₃.HCl: C, 61.24%; H, 5.87%; N, 3.40%. Found: C,61.12%; H, 5.85%; N, 3.36%.

BIOLOGICAL ACTIVITY

The biological activity of the compounds of the invention isdemonstrated by the data in Table 1.

                  TABLE 1    ______________________________________    5-HT.sub.1A Activity of Aminomethyl Benzodioxanes and Benzopyrans                  5-HT.sub.1A           Example                  IC.sub.50 *    ______________________________________           1      A           2      A           3      A           4      B           5      B           6      B           7      C           8      C           9      A           10     C           11     A           12     C           13     A    ______________________________________     *A: IC.sub.50  < 1 nM; B: IC.sub.50 = 1-5 nM; C: IC.sub.50 = 5-25 nM.

In vitro IC₅₀ test values for binding to the 5-HT_(1A) receptor weredetermined for representative compounds of Formula I by the method of S.J. Peroutka, Brain Research 344, 167 (1985); with only minormodifications. Test IC₅₀ values lower than 100 nM are considered toreflect activity at the 5-HT_(1A) receptor. Compounds with IC₅₀ valueslower than 25 nM comprise the preferred compounds.

The compounds comprising the present invention are selective agonistsand partial agonists at the serotonergic 5-HT_(1A) receptor.Serotonergic pathways are implicated in a variety of psychiatricdisorders such as anxiety and depression. It is also known that partialagonists of the 5-HT_(1A) receptor are clinically effective in thetreatment of anxiety (see: D. P. Taylor, "Serotonin Agents in Anxiety,"Annals of the New York Academy of Sciences vol. 600, entitled: "TheNeuropharmacology of Serotonin," pp 545-557, Oct. 15, 1990.)Furthermore, there is evidence that 5-HT_(1A) agents may be useful inthe prophylactic treatment of migraine (see: J. Pascual and J. Berciano,"An Open Trial of Buspirone in Migraine Prophylaxis. PreliminaryReport," Clinical Neuropharmacology 14:3, 1991, pp. 245-250). Compoundsof the present invention are thus envisioned to be useful in thetreatment of disorders such as anxiety, panic disorders,obsessive-compulsive disorder, and depression, as well as in theprophylactic treatment of migraine.

Reasonable variations, such as those which would occur to a skilledartisan, may be made herein without departing from the scope of theinvention.

We claim:
 1. A compound of Formula I or a pharmaceutically acceptablesalt, amide or hydrate thereof: ##STR9## wherein: R¹ and R² are bothhalogen;Cy is either ##STR10## (m=0, 1 or 2), with the phenylsubstituent at the 1 position of the cycloalkanyl or cycloalkenyl ringand the amino substituent at the 4 position; R³ and R⁴ are independentlyH or C₁₋₄ alkyl; and Y is CH₂.
 2. The compound of claim 1 wherein R³ andR⁴ are independently selected from hydrogen, methyl and ethyl.
 3. Apharmaceutical composition comprising an effective anxiolytic amount ofa compound of claim 1 and a pharmaceutically acceptable carrier.
 4. Amethod of treating anxiety comprising administering to a patient in needthereof an effective amount of a compound of claim 1.